Dialysis solutions are typically produced in central facilities of treatment centers and transferred via a tubing system to the individual treatment stations. Alternatively, treatment centers make use of large-volume canisters from which the prepared dialysis solution is conducted to the treatment stations. Such central supply installations for dialysis solutions are problematic with regard to their maintenance and the disinfection of the entire facility. Although these difficulties can be managed reliably, they cause undesirable expenditure.
A disadvantage of having a central supply of dialysis solution is also the lack of individualization in its production, as the needs of individual patients cannot be met by applying a customized composition of the dialysis solution during treatment.
It is therefore increasingly common to produce dialysis solutions directly at the treatment station from initial concentrates. This has the advantage of being able to produce large volumes of solution ready for use in treatment from a small amount of concentrate with minimal effort and being able to control the composition of the solution on an individual basis. A water source and a reverse osmosis (RO) system at the treatment station or close to the treatment station are the only additional components required.
The use of customary physiologically acceptable acidic components, such as hydrochloric acid or acetic acid necessitates a concentrate in a liquid form. Concentrates in a liquid form can be easily dosed by machine, and so the adjustment of solution compositions on an individual basis can be easily performed. More particularly, the composition can also be varied during dialysis treatments, providing possible therapeutic advantages in individual cases.
A disadvantage of the known solution concentrates is that both the production of the liquid form in manufacturing facilities and its transportation necessitates the expenditure of resources which would not be required in the case of solid initial concentrates. First, the container systems usually used for liquid concentrates have to exhibit certain properties. For example, they have to exhibit an appropriate resistance to being dropped, they have to ensure storage stability of the concentrates, and the container material needs to exhibit an appropriate buckling stability. Secondly, liquid concentrates, which are, for example, 125-fold concentrated, comprise a high concentration of acid, leading to a high acidity with pH values in the range from pH 0 to pH 1. Such a concentrate must be considered as hazardous material, which has to be handled professionally and with particular care in the case of accidents, leakages, etc.
Attempts have been made to avoid liquid concentrates and to provide the concentrate in a solid form. However, individualization of the final dialysis solution is then only achieved with considerable effort. Various dry initial concentrates of different compositions can be produced that may be adapted for individual use. For example, variation of the potassium constituents is desired in order to provide dialysis solutions of different potassium concentrations which are customized to fulfil different patient needs.
Dry concentrates are of particular interest for producing a dialysis batch. Here, the entire volume of dialysis solution is produced in one dissolving process and provided for dialysis.
The typical components for the production of a dialysis solution are magnesium chloride, calcium chloride, sodium chloride, potassium chloride, sodium bicarbonate, glucose and a physiologically acceptable acid such as hydrochloric acid, acetic acid or citric acid. In the case of a solid formulation, only solid acids are conceivable as acidic components. In general, liquid acids may partially dissolve the concentrate, which results in a different dosage form, i.e., in a slurry (a suspension with a high solid content).
The combination of the components can lead to physical/chemical incompatibilities, resulting in possible deterioration of the dissolution behaviour of the concentrate and impairing the storage stability.
For example, it is known from the prior art that glucose, which is typically used as an osmotic agent, is not stable when stored together with other components of the concentrate such as citric acid or sodium bicarbonate. However, glucose has a high osmolarity at relatively low concentrations and is well tolerated. A particular advantage of the use of glucose is its relatively low price as compared to other excipients that could be potentially used as osmotic agents.
Various suggestions are known in the prior art to avoid the interaction between glucose and other components in dry concentrates.
EP 1 192 960 B1, EP 1 192 961 B1, JP 200823958, EP 1 086 700 B1 and EP 1 059 083 B1 describe dry concentrates in which granules are formed as multiple layers of the components required for dialysis solution production. Glucose layers, or areas of glucose within a layer, are separated from the other components by separating layers in order to avoid a chemical interaction and/or a degradation of the glucose. The separating layer consists of, for example, sodium chloride.
However, a disadvantage of such granules is that glucose is in contact with sodium chloride, which can lead to caking after prolonged storage. Caking is the process of agglomerate formation of a primarily powdery substance, of granules or of a substance in the form of pellets or tablets. Caking occurs as particles bind and stick together during processes of partial dissolution or other diffusion phenomena. Caking is promoted by the influence of water and heat.
Furthermore, the required electrolyte components magnesium chloride and calcium chloride are hygroscopic and have a tendency to partially form slurries with their hydration water. Slurries comprise solid and dissolved excipients side by side in a liquid phase. The solid content of such a mixture is so high that the appearance is predominated by a pulpy or pasty viscosity.
For the stable storage of dry concentrates, JP 3589489 B2 and EP 1 458 433 A1 suggest to provide the components required for the dialysis solution in multiple layers within one container, wherein glucose is provided with a separating layer of sodium chloride separate from a further, possibly interactive layer, e.g. sodium bicarbonate. The problem of slurry formation caused by the hygroscopy of the components magnesium chloride and calcium chloride is, however, not addressed, and also the problem of caking of glucose and sodium chloride remains unresolved.
JP 2001340423 A2 suggests storing glucose separate from other components in order to avoid the caking of glucose or to avoid degradation of glucose through interaction with other components. However, the problem of slurry formation caused by the electrolyte components magnesium chloride and calcium chloride persists.